The abundance of metabolites related to protein methylation correlates with the metastatic capacity of human melanoma xenografts.

Abstract

Metabolic reprogramming is a major factor in transformation, and particular metabolic phenotypes correlate with oncogenotype, tumor progression, and metastasis. By profiling metabolites in 17 patient-derived xenograft melanoma models, we identified durable metabolomic signatures that correlate with biological features of the tumors. BRAF mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF wild-type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML). TML levels correlated with histone H3 trimethylation at Lys9 and Lys27, and methylation at these sites was also enhanced in efficiently metastasizing tumors. Erasing either of these marks by genetically or pharmacologically silencing the histone methyltransferase SETDB1 or EZH2 had no effect on primary tumor growth but reduced cellular invasiveness and metastatic spread. Thus, metabolite profiling can uncover targetable epigenetic requirements for the metastasis of human melanoma cells.

• Authors: Xiaolei Shi, Alpaslan Tasdogan, Fang Huang, Zeping Hu, Sean J Morrison, Ralph J DeBerardinis
• Journal: Science advances (Sci Adv) Vol. 3 Issue 11 Pg. eaao5268 (11 2017) ISSN: 2375-2548 [Electronic] United States
• PMID: 29109980 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GSK-2816126
• Histones
• Indoles
• Pyridones
• RNA, Small Interfering
• Protein Methyltransferases
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Histone-Lysine N-Methyltransferase
• SETDB1 protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Cell Movement (drug effects)
• Down-Regulation (drug effects)
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors, genetics, metabolism)
• Histone-Lysine N-Methyltransferase
• Histones (metabolism)
• Humans
• Indoles (pharmacology, therapeutic use)
• Melanoma (drug therapy, metabolism, pathology)
• Metabolome
• Metabolomics
• Methylation (drug effects)
• Mice
• Mice, Inbred NOD
• Neoplasm Metastasis
• Principal Component Analysis
• Protein Methyltransferases (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Pyridones (pharmacology, therapeutic use)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Transplantation, Heterologous